Alzheimer's disease is the most common neurodegenerative disorder worldwide. It is characterized by the accumulation of senile plaques in the brains of the affected individuals. The senile plaques consist largely of β-amyloid peptide, derived from proteolytic processing of the β-amyloid precursor protein, β-APP.
While in the majority of cases, Alzheimer's appears to occur as a sporadic disease, in a significant patient population it is genetically inherited as an autosomal dominant trait (familial Alzheimer's disease, FAD). FAD has been determined to be due to mutations in presenilin proteins, PS1 and PS2 (Sherrington et al., Nature 375:754–760 (1995); Levy-Lahad et al., Science 269:973–977 (1995); Rogaev et al., Nature 376:775–778 (1995)). These mutations lead to a gain-of-function which contributes to an early onset and aggressive progression form of Alzheimer's diseases. PS1 and PS2 are ubiquitously expressed as multi-membrane spanning proteins in all mammalian cells examined. The PS proteins display an intracellular localization (both are located in the endoplasmic reticulum (ER) and early Golgi) where they carry out a number of different biological activities, including involvement in cell survival and apoptosis, and specifically Wnt/Wg and Notch signaling.
Numerous reports implicate a role of PS proteins in cell survival and apoptosis. Cells expressing FAD PS appear to be more vulnerable to apoptosis (Wolozin et al., Science 274:1710–1713 (1996)); Guo et al., J. Neurosci. 17:4212–4222 (1997); Deng et al., FEBS Lett. 397: 50–54 (1996)). Likewise, transgenic mice engineered to express FAD PS display a propensity of neuronal death both naturally (Chui et al., Nature Med. 5:560–564 (1999)) and resulting from injury (Gub et al., Nature Med. 5:101–106 (1999)). PS1 is also down-regulated in cell models of p53 mediated apoptosis, again suggesting a critical role for PS in cellular survival (Roperch et al., Nature Med. 4:835–838 (1998)).
PS1 has been observed to physically associate with members of the Wnt/Wg signaling pathway, specifically β-catenin (Yu et al., J. Biol. Chem. 273:16470–16475 (1998); Murayama et al., FEBS Lett. 433:73–77 (1998)) and glycogen synthase kinase 3β (GSK 3β) (Takashima et al., Proc. Natl. Acad. Sci. USA 95:9637–9641 (1998)). Stimulation of the Wnt/Wg pathway transduces an intracellular signal to the nucleus, which activates select genes required for differentiation and/or cell survival. To deliver this signal, GSK 3β is inactivated resulting in the stabilization of β-catenin, followed by translocation of β-catenin to the nucleus where it associates with Tcf/Lef transcription factors to initiate expression of downstream genes. The mechanism by which PS1 affects β-catenin stability is not presently known. However, FAD PS1 reduces both β-catenin stability (Zeng et al., Nature 395:698–702 (1998)) and nuclear translocation (Nishimura et al., Nature Med. 5:164–169 (1999)). FAD PS1 also shows an increased association with GSK 3β as compared to normal PS 1 (Takashima et al., supra).
The role for PS in Notch signaling of cell differentiation is primarily based on genetic evidence. Gene ablation experiments in which PS1 and/or PS2 genes are inactivated results in a developmental lethal phenotype in mouse identical to Notch 1 inactivation (Herreman et al., Proc. Natl. Acad. Sci. USA in press). The genetic homolog of mammalian PS in C. elegans, sel-12, is essential for Notch signaling in this animal (Levitan and Greenwald, Nature 377:351–354 (1995)). Mutations in sel-12 result in Notch signaling defects, which can be rescued by the human PS genes (Baumeister et al., Genes & Function 1:149–159 (1997)). This signaling pathway involves protein processing of Notch where PS appears to mediate this proteolytic step, either directly or indirectly (De Strooper et al., Nature 398:518–522 (1999); Song et al., Proc. Natl. Acad. Sci. USA 96:6959–6963 (1999)).
For further details about the structure and biological role of presenilins see, for example, Haass, Neuron 18:687–690 (1997), Annaert and Strooper, TINS 22:439–444 (1999) and Thinakaran, J. Clin. Invest. 140:1321–1327 (1999).
Another protein that may play a role in the neuronal loss in Alzheimer's disease is Par-4. Par-4, a protein recently implicated as a mediator of prostate cancer, melanoma, and neuronal cell death, has been found to be elevated in vulnerable regions of the Alzheimer's disease brain (Guo et al., Nature Med. 4:957–962 (1998)). Par-4 expression is also elevated in cultured cells expressing FAD PS1 (Guo et al., supra). Inhibition of Par-4 expression or function can prevent neuronal apoptotic cell death induced by β-amyloid or neurotrophic factor withdrawal. In addition, Par-4, has been found to specifically interact with the regulatory domain of atypical protein kinase C subfamily of isoenzymes (aPKCs), which dramatically inhibits their enzymatic activity (Diaz-Meco et al., Cell 86:777–786 (1996)).
The aPKC subfamily has recently been the focus of considerable attention. It is composed of two members, ζPKC and ξ/ζPKC, which appear to be involved in a number of important cellular functions including cell proliferation and survival. The aPKCs selectively bind to, and are inhibited by, Par-4. Consistently, the ectopic expression of Par-4 induces apoptosis in a manner that is dependent on its ability to bind to, and inhibit the aPKCs (Diaz-Meco et al., J. Biol. Chem. 274:19606–19610 (1999)).
While there are numerous factors and pathways that have been implicated in neuronal degeneration, and specifically in Alzheimer's disease, the interaction and relationship of these factors and pathways is not well understood. A better understanding of the cellular mechanisms by which the PS and Par-4 genes exert their biological functions would contribute substantially to our knowledge of the molecular mechanisms causing various neurodegenerative disorders, such as Alzheimer's disease, and is pivotal for the identification and development of drug candidates for the treatment of such diseases.